The selectin family of cell adhesion molecules, together with their glycoconjugate ligands, participate in leukocyte trafficking to sites of inflammation and to lymphoid organs. P- and E-selectins are expressed on activated vascular endothelial cells where they mediate initial tethering and rolling of leukocytes on endothelial cells by binding to P-selectin glycopeptide ligand-1 (PSGL-1) present on the surface of leukocytes. P-selectin is also expressed on activated platelets. L-selectin is expressed on the surface of leukocytes and mediates leukocyte-leukocyte interactions by binding to PSGL-1 present on the surface of other leukocytes promoting leukocyte accumulation to the inflammatory sites. Selectins recognize the sialyl Lewis x epitope (SLex, NeuAcα2-3Ga1β1-4(Fucα1-3)GlcNAcβ1-) on glycoconjugate ligands. However, selectin binding to SLex determinant alone is low affinity and is necessary but not sufficient for physiological interactions. Thus, selectins require additional post-translational modifications or peptide components for high-affinity binding to their ligands. P- and L-selectin both bind to the extreme N-terminus of PSGL-1 and interact with three clustered tyrosine sulfate residues and a nearby core-2-based O-glycan with sialyl Lewis x epitope (C2—SLex). The N-terminus of human PSGL-1 contains three potential tyrosine sulfation sites (Y46, Y48 and Y51) and two potential O-glycan attachment sites (T44 and T57).
Leppanen et al. report that binding of glycosulfopeptides to P-selectin implicates stereospecific contributions of individual tyrosine sulfate and sugar residues. J Biol Chem., 2000, 275(50):39569-39578. Leppanen et al. also report that human L-selectin preferentially binds synthetic glycosulfopeptides modeled after endoglycan. Glycobiology, 2010, 20(9):1170-1185. See also WO 2003/032925, WO 99/65712, US 2002/0026033, U.S. Pat. No. 5,858,994, U.S. Pat. No. 6,136,790, Hicks et al. FASEB J, 2002, 16(11):1461-1462, and Hicks et al. FASEB J, 2002, 16(5):A1052.
Ohta et al. report inhibition of P-selectin specific cell adhesion by a low molecular weight, non-carbohydrate compound, KF38789. Inflamm Res, 2001, 50(11):544-51.
Several small molecule inhibitors and protein therapeutics aimed at blocking PSGL-1/P-selectin interactions are already in clinical trials. Certain candidates pose production, stability, and immunity issues. Thus, there is a need for molecules that bind to selectins with high specificity and affinity, which in turn inhibit selectin mediated cell-cell interactions that have desirable pharmacological properties.
References cited herein are not an admission of prior art.